Several cancer-derived missense mutations in the CDKN2A gene result in substitution of arginine residues in the C-terminal arginine-rich region of p14ARF ( CDKN2A-4). p14ARF mutants p14ARF R81G, p14ARF R82C, p14ARF R87C, p14ARF R88Q, p14ARF R90H, p14ARF R98Q, p14ARF R99C and p14ARF R98L;R99S are unable to bind to C1QBP (p32) and they do not localize to mitochondria. Binding of these mutants to other p14ARF interacting proteins, such as MDM2 and NPM1 (B23), remains unaffected. Mutations in p14ARF that affect binding to C1QBP interfere with p53-mediated apoptosis (Itahana and Zhang 2008).
Missense mutations affecting arginine residue R98 have also been reported to affect p14ARF localization to nucleolus and to diminish, due to partial mislocalization, the ability of p14ARF to sequester MDM2 (Zhang et al. 1999).